Autosomal Recessive Cerebellar Ataxias in South America: A Multicenter Study of 1338 Patients

Afiliação

(1)    Ataxia Unit, Department of Neurology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.

(2)    Neurology Section, Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Brazil.

(3)    Neurology Service, Hospital Geral de Fortaleza, Fortaleza, Brazil.

(4)    Neurology, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil.

(5)    Medical Genetics Service, Hospital Universitário Professor Edgard Santos, Salvador, Brazil.

(6)    Neurogenetics Research Center, Instituto Nacional de Ciencias Neurológicas, Lima, Peru.

(7)    Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru.

(8)    CETRAM-Centro de Estudios de Transtornos del Movimiento, Santiago, Chile.

(9)    Hospital San Borra Arriarán, Santiago, Chile.

(10)Neurogenetics Unit, Hospital General de Agudos José Maria Ramos Mejía, Buenos Aires, Argentina.

(11)Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

(12)Centros de Pesquisa Clínica e Experimental, e Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

(13)Department of Neurology, University of Campinas (UNICAMP), Campinas, Brazil.

(14)Department of Neuroscience and Behavioural Science, School of Medicine, University of São Paulo (USP), Ribeirão Preto, Brazil.

(15)Internal Medicine Department, Federal University of Paraná, Curitiba, Brazil.

(16)Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, Tübingen, Germany.

(17)German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

Resumo

Autosomal recessive cerebellar ataxias (ARCAs) comprise complex genetic ataxia disorders with variable central and peripheral nervous system involvement and systemic changes. They can overlap with other conditions such as hereditary spastic paraplegia, inborn errors of metabolism, and genetic encephalopathies.1 While usually starting in childhood or young adulthood, late adult-onset may occur. The advanced application of next-generation sequencing has allowed the molecular definition of many previously undetermined ARCAs in the last decade, including many new ARCA genes. There are few reports of epidemiology of ARCA and its frequency in South America. Integration between the ataxia centers in South America is mandatory to better capture the frequency and types of ARCA across this large continent, in particular when now preparing for large-scale natural history and treatment trials in ARCAs. This multicenter study aimed to retrospectively capture the frequency of the most common forms of ARCA across South America, combining data from 11 large ataxia centers in South America: one in Argentina, one in Chile, one in Peru, and eight in Brazil. Data from each ataxia center were captured via a standardized questionnaire that included the following questions: (A) number of ARCA patients, defined as an ataxia patient with (i) a molecularly confirmed ARCA diagnosis or (ii) ataxia onset before age 40 years and negative but informative family history; (B) number of ARCA patients with genetic diagnosis versus no genetic diagnosis as of yet; and (C) number of patients of each genetic ARCA subtype. The frequency of patients with specific genotypes was analyzed. A total of 1338 patients were included in this study making it the largest ARCA frequency study to date. In South America, 43% of patients had a positive molecular diagnosis confirming the genetic etiology of ARCA. Friedreich's ataxia was the most common ARCA and corresponded to 57% of the cases with a molecular diagnosis. The second most common form of ARCA was RFC1 (8%), followed by ataxia telangiectasia (AT) (7%), Niemann–Pick type C (4%), ARSACS (4%), ataxia with oculomotor apraxia (AOA) type 2 (3%), AOA type 4 (2%), and SYNE1 ataxia (2%). Other less common forms of ARCA represented 13% of the cases, including AOA type 1, ANO10, and STUB1. This is the first multicentric study that provides information about epidemiology and frequency of ARCA in South America, and the largest ARCA frequency study worldwide. Our data are compatible with the literature regarding the most common forms of ARCA, but highlight the fact that ARSACS and NPC1 might be more common than previously thought, and provide the first real-world frequency estimates for the fairly recently identified RFC1 ARCA. This study is limited by its retrospective nature. Also, it is possible that patients with undetermined ataxia are still poorly investigated through exome sequencing in South America. This, however, renders our population an interesting opportunity to identify new genes and knowledge on epidemiological features in ARCA. Moreover, our observations are relevant to the current planning of upcoming gene therapy and clinical trials in ARCAs.